Targeted removal of PML-RARα protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia

Jing, Yongkui; Xia, Lijuan; Waxman, Samuel

doi:10.1182/blood.v100.3.1008

Cited by 36 publications

(23 citation statements)

References 42 publications

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“…Previous studies have found that all-trans-retinoic acid increases Bcl2a1 mRNA levels and decreases apoptosis in the NB4 and PBL985 acute promyelocytic leukemia cell lines (55)(56)(57)(58). In a more recent study with PBL985 cells, 9-cis-retinoic acid increased Bcl2a1 expression but the RXR-selective agonist SR11237 did not (59).…”

Section: Discussionmentioning

confidence: 96%

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Rasooly

Schuster

Gregg

et al. 2005

The Journal of Immunology

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Vitamin A affects many aspects of T lymphocyte development and function. The vitamin A metabolites all-trans- and 9-cis-retinoic acid regulate gene expression by binding to the retinoic acid receptor (RAR), while 9-cis-retinoic acid also binds to the retinoid X receptor (RXR). Naive DO11.10 T lymphocytes expressed mRNA and protein for RAR-α, RXR-α, and RXR-β. DNA microarray analysis was used to identify RXR-responsive genes in naive DO11.10 T lymphocytes treated with the RXR agonist AGN194204. A total of 128 genes was differentially expressed, including 16 (15%) involved in cell growth or apoptosis. Among these was Bcl2a1, an antiapoptotic Bcl2 family member. Quantitative real-time PCR analysis confirmed this finding and demonstrated that Bcl2a1 mRNA expression was significantly greater in nonapoptotic than in apoptotic T lymphocytes. The RXR agonist 9-cis-retinoic acid also increased Bcl2a1 expression, although all-trans-retinoic acid and ligands for other RXR partner receptors did not. Treatment with AGN194204 and 9-cis-retinoic acid significantly decreased apoptosis measured by annexin V staining but did not affect expression of Bcl2 and Bcl-xL. Bcl2a1 promoter activity was examined using a luciferase promoter construct. Both AGN194204 and 9-cis-retinoic acid significantly increased luciferase activity. In summary, these data demonstrate that RXR agonists increase Bcl2a1 promoter activity and increase expression of Bcl2a1 in naive T lymphocytes but do not affect Bcl2 and Bcl-xL expression in naive T lymphocytes. Thus, this effect on Bcl2a1 expression may account for the decreased apoptosis seen in naive T lymphocytes treated with RXR agonists.

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Section: Discussionmentioning

confidence: 96%

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Rasooly

Schuster

Gregg

et al. 2005

The Journal of Immunology

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“…We and other groups have found that ATRA and As 2 O 3 proteolized PML-RARa differently (Jing et al, 2001;Zhu et al, 2001). Thus, ATRA, unlike As 2 O 3 , leads to a decrease in full-length PML-RARa with formation of a specific 85 kDa fragment product, termed DPML-RARa in NB4 cells (Figure 2a) Gianni et al, 1998;Fanelli et al, 1999;Idres et al, 2001;Jing et al, 2001;Jing et al, 2002). DPML-RARa appears to delete the N-terminal portion of PML, since the RARa antibody used is against the C-terminal RARa region.…”

Section: Discussionmentioning

confidence: 99%

The cleavage product ΔPML–RARα contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells

et al. 2003

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PML-RARa protein, the leukemogenic product of t (15,17) in acute promyelocytic leukemia, is cleaved into a truncated form termed DPML-RARa during all-trans retinoic acid (ATRA)-induced differentiation of NB4 cells. DPML-RARa is not formed in ATRA differentiation resistant NB4 subclones. As 2 O 3 inhibits DPMLRARa formation and differentiation-induction when given in combination with ATRA. Treatment with hexamethylene bisacetamide (HMBA) combined with ATRA enhances ATRA-induced differentiation in ATRAinsensitive NB4-CI and arsenic-resistant NB4/As cells, and is associated with stabilization of PML-RARa protein and increased DPML-RARa formation. Unlike forced expression of PML-RARa, forced DPML-RARa expression based on an estimated deletion of the Nterminal PML portion does not repress RARE-tk-luc reporter activity mediated by endogenous retinoic acid receptors. The cleavage of PML-RARa is blocked by RARa antagonist Ro-41-5253 and cycloheximide and therefore requires a RARa transactivation-dependent pathway. Proteasome inhibitor MG-132 and caspase inhibitor Z-VAD-FMK do not block ATRA-induced PML-RARa cleavage and differentiation. These data suggest that (a) ATRA treatment induces PML-RARa cleavage by induction of unknown enzymes independent of proteasome-and caspase-mediated pathways; (b) DPMLRARa might function differently from both PML-RARa and RARa; (c) failure to cleave PML-RARa and form DPML-RARa after ATRA treatment may contribute to ATRA resistance in APL cells.

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“…Combination of ATRA and HDAC inhibitors has been found to synergize in differentiation of t(15;17)-positive APL cell line NB4 [34] and to overcome the differentiation block in ATRA-resistant t(11;17)-positive leukemic cells [10]. Besides differentiation, the combined treatment with ATRA and HDAC inhibitors may induce cell death as well.…”

Section: Discussionmentioning

confidence: 99%

Neutrophilic differentiation modulates the apoptotic response of HL-60 cells to sodium butyrate and sodium valproate

Vrba¹,

Doležel²,

Ulrichová³

2010

neo

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Histone deacetylases (HDACs) play an important role in regulation of gene expression. Since aberrant upregulation of their activity has been linked to various cancers including leukemic disorders, inhibition of HDACs has emerged as a potential strategy in anticancer therapy. The short chain fatty acids, butyrate and valproate (2-propylvalerate) are effective as HDAC inhibitors at millimolar concentrations [1]. They have been shown to induce, depending on their concentration, monocytic differentiation [2-4] and/or apoptosis in several types of human myeloid leukemic cells [3,[5][6][7]. HDACs have been also identified as molecular targets of all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL) [8]. Neutrophilic differentiation of normal myeloid cells by ATRA is mediated through the nuclear retinoic acid receptor α (RARα). In the absence of ligand, RARα interacts with nuclear corepressor proteins to form a complex including HDAC1 or HDAC2, resulting in transcriptional repression or silencing. Physiological concentrations of ATRA induce dissociation of the nuclear repressor complex and recruitment of coactivators with histone acetyltransferase activity. This permits the transcriptional activation of differentiation-related genes. In APL cells, the gene encoding RARα appears to be involved in chromosomal translocations, producing several types of RAR-fusion proteins [8,9]. Approximately 98% of APL cases have the t(15;17) translocation leading to the PML-RARα (promyelocytic leukemia protein/RARα) fusion protein. Although ATRA binds to PML-RARα with an affinity comparable to normal RARα, the dissociation of the nuclear repressor complex from PML-RARα and subsequent differentiation occur only at pharmacological doses of ATRA. In contrast, a less common variant of APL with the t(11;17) translocation and the resultant PLZF-RARα (promyelocytic zinc finger protein/RARα) fusion protein has been found resistant to ATRA. This resistance arises from the presence of additional binding site for the nuclear repressor complex in the PLZF moiety of the fusion protein which is insensitive to Received February 3, 2010Differentiation of myeloid leukemic cells may result in less sensitivity to various apoptotic stimuli. We examined whether human leukemia HL-60 cells differentiating by all-trans retinoic acid (ATRA) acquired resistance to the apoptogenic activity of two histone deacetylase (HDAC) inhibitors, butyrate and valproate. In undifferentiated cells, the cytotoxicity of both butyrate and valproate was associated with activation of the intrinsic apoptotic pathway since we observed dissipation of mitochondrial membrane potential, induction of caspase-9 and caspase-3 activities, appearance of sub-G1 DNA and loss of plasma membrane asymmetry and/or integrity. Both HDAC inhibitors were also able to induce accumulation of undifferentiated cells in the G0/G1 phase of the cell cycle. ATRA was found to enhance the apoptotic effect of both butyrate and valproate in undifferentiated cells. This aside, ATRA ...

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Targeted removal of PML-RARα protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia

Cited by 36 publications

References 42 publications

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

The cleavage product ΔPML–RARα contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells

Neutrophilic differentiation modulates the apoptotic response of HL-60 cells to sodium butyrate and sodium valproate

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